JP5694623B2 - 遺伝子操作した動物から得られるヒトポリクローナル抗体 - Google Patents
遺伝子操作した動物から得られるヒトポリクローナル抗体 Download PDFInfo
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- JP5694623B2 JP5694623B2 JP2000597321A JP2000597321A JP5694623B2 JP 5694623 B2 JP5694623 B2 JP 5694623B2 JP 2000597321 A JP2000597321 A JP 2000597321A JP 2000597321 A JP2000597321 A JP 2000597321A JP 5694623 B2 JP5694623 B2 JP 5694623B2
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Description
技術分野
本発明の分野は、ヒトの予防的および治療的処置のための実質的にはヒトポリクローナル抗血清である。
細菌、真菌、ウイルスおよび寄生虫によって引き起こされる感染性疾病の治療は、主に化学療法に基づいている。しかし、薬剤耐性生物の発生は、新たな抗生物質の継続的開発が要求される。同時に、感染の制御は、新たな病原体の発生によって脅されている。栄養失調、AIDS、癌の医療的治療、自己免疫疾病および臓器移植により増加する免疫無防備状態の個体の数は、抗生物質療法の効力を減少させ、感染を制御する困難さを増大させる。
感染性疾病における抗体基本の療法は、最近、A.CasadevallおよびM.D.Scharff、Clinical Infectious Diseases 150−161頁;1995年によって再検討された。
遺伝的に改変された軽および重鎖免疫グロブリン遺伝子座および少なくともヒト軽および重鎖免疫グロブリン遺伝子座の一部を含むトランスジェニック家畜が、供給されることを特徴とする、特異的抗原に対する実質的にヒトポリクローナル抗血清の産生の方法が提供される。前記方法は、抗体レパートリーが、遺伝子変換によって優先的に多様化される家畜(例えば、ウサギ、ヒツジ、ブタ、ウシ)の段階的修飾を使用する。前記方法は、対応のヒト等価物との免疫グロブリン遺伝子座の内因性要素の相同的組換えによる置換、特に、重および軽鎖の定常領域、およびD領域の遺伝子座に近傍のものを含めた1種または数種の可変部要素をコードする1種または数種のエキソンの置換に関与する。抗体多様性が、遺伝子変換によって優先的に発生される動物では、ヒトV領域要素に、主にD領域に近傍のV領域を置換することは、免疫グロブリンの大半でのヒトV要素の発現を生じる。この遺伝子操作に続いて、同じ種の宿主を交配し、そして宿主グリコシル化を用いた実質的にヒトの抗血清の産生で免疫化に応答する能力のある宿主について選択し、免疫グロブリンは、ヒト重鎖の少なくとも機能的部分を有する。実質的にヒトのタンパク質配列免疫グロブリンを発現する動物を、目的の免疫原、特に、治療活性を示す抗体産生を開始させる免疫原との免疫化によるポリクローナル抗体製品の生成のために使用する。抗血清の精製後、このような抗血清を、それ自身または、感染性試薬、悪性細胞、癌、歓迎されない標的細胞または免疫調節の消耗のための他の試薬との組み合わせで使用し得る。
宿主を免疫原で免疫化させることによって、異種宿主中で実質的にヒトの抗血清を生成する方法が提供される。宿主は、内因性抗血清を産生する能力が少なくとも実質的になく、免疫原物質に露出することにより実質的にヒトのポリペプチド抗血清を優先的に産生する能力のあること;免疫グロブリン遺伝子座を転位し、V、(DH)、JおよびC領域を組換えて、実質的にヒトのタンパク質抗血清を産生させるそれの能力を保持することによって特徴づけられ、少なくとも1つのヒト免疫グロブリン定常領域および/または少なくとも1つのヒト可変(V)部要素を含む。特に目的であるのは、Cγサブクラス1、2、3および4のいずれかを含めたCαまたはCγのサブクラスの定常領域である。ヒト定常領域および可変部をコードするDNA断片は、対応する内因性要素の相同的組換えおよび置換によって、ゲノムに組込まれる。
実質的にヒトの免疫グロブリンを発現するトランスジェニック・ウサギの発生
ヒト定常領域要素および可変部要素をコードするエキソンは、相同的組換えによりウサギ線維芽細胞のゲノムに組込まれる。ウサギ線維芽細胞を、ヒト免疫グロブリン遺伝子座要素を含む種々の線状DNA構築物と形質移入させる。成功裏に形質移入した細胞を選択し、そしてウサギのクローニングに使用する。
成熟オランダ・ベルトンウサギを、毎12時間(0.3mg×2および0.4mg×4)に、濾胞刺激ホルモン(FSH)の皮下注射によって過剰排卵させる。卵発生は、最後のFSH注射の12時間後に、0.5mgの黄体形成ホルモン(LH)の静脈注射によって誘導される。卵母細胞は、LH注射の17時間後の卵管洗浄によって回収される。卵母細胞は、成熟の16〜19時間後に機械的に除核される。染色体除去は、紫外線下で、bisBENSIMIDE(ホエスト33342、ミズーリー州セントルイスのシグマ)染料で評価する。
遺伝子操作したウサギ(上に記述されるとおり)に、0日目および14日目に、精製B型肝炎表層抗原(HBsAg)(不完全フロイントアジュバント中10μg)を筋肉内に免疫した。28日目に、動物を、耳から出血させ、そして血清を作成する。ELISAプレート(NUNC、デンマーク)に、1時間、室温で、PBS中の1μg/mlのHBsAgを被覆させる。続いて、利用可能な結合部位は、PBS中1%非脂肪スキムミルク(NFM)(300μl/ウエル)でのインキュベーションによって遮断される。ウサギ血清を、PBS/1%NFMに希釈し、そして被覆ウエルに添加する。1時間のインキュベーションの後、プレートを、3回、PBS/0.05%ツイーン20で洗浄し、そして結合Igを、西洋ワサビペルオキシダーゼで接合させたヤギ抗ヒトIgを使用して検出する。接合ヤギ抗体を、1mg/mlでo−フェニレンジアミン・ジヒドロクロリド(シグマ)を使用して検出する。比色反応を、1M HCl溶液の添加によって停止させ、そして吸光度を、490nmで測定する。対照として、非免疫ウサギから得た血清を、使用する。非免疫ウサギから得た血清は、HBsAgと反応しない。1:100の希釈で、未被覆およびHBsAg被覆ウエルで測定した光学密度は、0.4未満である。対照的に、免疫ウサギから得た血清は、HBsAgと反応性のある実質的にヒトの抗体を含有する。1:100の血清希釈で、測定された光学密度は、2.8である。血清のさらなる希釈で、測定された光学密度は、0.2に(25600の希釈で)減少する。ヤギ抗ウサギIgG−HRP接合体と反応性のある抗体は、まったく検出されない。これは、遺伝子操作したウサギは、免疫化に続く実質的にヒトの抗−HBsAg抗体を産生することを示す。
HBsAgを発現するヒト肝癌腫セルラインを、1時間、37℃で、100ulのPBS中の0.1mCi51Crで標識する。2千個の51Cr標識細胞を、抗−HBsAg免疫グロブリンを発現する遺伝子操作したウサギから得た血清(上記参照)とインキュベートする。37℃で、2時間後、上清への51Crの放出は、シンチレーション測定装置を用いて放射活性を測定することによって測定される。最大限の放出の測定のために、1%トリトン×100を添加する。細胞溶解の程度は、以下のとおり計算される:
溶解率(%)=実験的CPM±自発的CPM数/CPM総数±自発的CPM。非免疫化ウサギから得た血清(1:30に希釈)との標識細胞のインキュベーションは、細胞溶解(<10%)を生じる。しかし、免疫化ウサギから得られる血清を用いた細胞のインキュベーションは、80%細胞溶解を引き起こす。加熱処理(30分間、56℃)による血清中の補体の不活性化は、免疫化ウサギから得た血清を不活性にさせる。これらの結果は、遺伝子操作したウサギによって産生される実質的にヒトの抗体は、HBsAg陽性細胞に結合し、そして補体依存性溶解を引き起こすことを示す。
実質的にヒトの免疫グロブリンを、硫酸アンモニウム沈降およびイオン変換クロマトグラフィーにより、遺伝子操作したウサギの血清から精製する。SCIDマウスに、HBsAgを発現する百万個のヒト肝臓癌腫細胞を注射する。続いて、25μgの免疫グロブリンを、日当たり一回腹膜に注射する。非免疫化ウサギ血清から単離される抗体で処置した動物は、約60日後に死ぬ。これは、肝臓癌腫細胞の未処置受容者に類似する。対照的に、免疫化ウサギ血清から単離される抗体で処置されるマウスは、150日以上の間生存する。これは、遺伝子操作されるウサギで産生されるヒト抗体は、SCIDマウスからヒト癌腫細胞を排出する能力のあることを示す。
Claims (3)
- ウサギ重鎖定常領域がヒト重鎖定常領域に置換され、及び、ウサギ重鎖可変領域のうち、D領域遺伝子座に近傍の1種または数種のV領域要素をコードするエキソンが、1種または数種のヒトのV領域要素をコードするエキソンに置換された免疫グロブリン遺伝子を有するトランスジェニックウサギから生産される、免疫原に特異的結合をするウサギのポリクローナル抗血清組成物。
- 前記ウサギが、遺伝子変換により抗体多様性を生じる、請求項1に記載のポリクローナル抗血清組成物。
- 前記ウサギが、ウサギ目からのものである、請求項1に記載のポリクローナル抗血清組成物。
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WO2000046251A2 (en) * | 1999-02-05 | 2000-08-10 | Buelow Jens Ulrich | Human polyclonal antibodies from transgenic nonhuman animals |
WO2001019394A2 (en) * | 1999-09-15 | 2001-03-22 | Therapeutic Human Polyclonals, Inc. | Immunotherapy with substantially human polyclonal antibody preparations purified from genetically engineered birds |
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US20050144655A1 (en) | 2000-10-31 | 2005-06-30 | Economides Aris N. | Methods of modifying eukaryotic cells |
US6586251B2 (en) * | 2000-10-31 | 2003-07-01 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US6596541B2 (en) | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
JP2002316944A (ja) * | 2001-04-17 | 2002-10-31 | Chemo Sero Therapeut Res Inst | ヒトポリクローナル抗体組成物 |
AU2003290689A1 (en) | 2002-11-08 | 2004-06-03 | Kyowa Hakko Kirin Co., Ltd. | Transgenic ungulates having reduced prion protein activity and uses thereof |
CN1852925A (zh) | 2003-07-15 | 2006-10-25 | 人类多克隆治疗公司 | 人源化免疫球蛋白基因座 |
NZ550106A (en) | 2004-04-22 | 2009-06-26 | Kyowa Hakko Kirin Co Ltd | Transgenic animals and uses thereof |
ATE536374T1 (de) | 2006-09-01 | 2011-12-15 | Therapeutic Human Polyclonals Inc | Erhöhte expression von humanem oder humanisiertem immunglobulin bei nicht-humanen transgenen tieren |
SG10202006332PA (en) * | 2015-10-29 | 2020-08-28 | Hoffmann La Roche | Transgenic rabbit with common light chain |
CN111511400A (zh) | 2017-12-29 | 2020-08-07 | 豪夫迈·罗氏有限公司 | 抗vegf抗体及其使用方法 |
CN112004411B (zh) * | 2018-03-21 | 2023-05-26 | 晶体生物科学股份有限公司 | 产生人抗体的转基因鸡 |
KR20210133234A (ko) | 2019-02-18 | 2021-11-05 | 바이오사이토젠 파마슈티컬스 (베이징) 컴퍼니 리미티드 | 인간화 면역글로불린 유전자좌를 갖는 유전적으로 변형된 비-인간 동물 |
EP3990492A1 (en) | 2019-06-27 | 2022-05-04 | F. Hoffmann-La Roche AG | Novel icos antibodies and tumor-targeted antigen binding molecules comprising them |
AR119382A1 (es) | 2019-07-12 | 2021-12-15 | Hoffmann La Roche | Anticuerpos de pre-direccionamiento y métodos de uso |
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WO2000046251A2 (en) * | 1999-02-05 | 2000-08-10 | Buelow Jens Ulrich | Human polyclonal antibodies from transgenic nonhuman animals |
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US20020178456A1 (en) | 2002-11-28 |
CA2362098A1 (en) | 2000-08-10 |
JP2002540069A (ja) | 2002-11-26 |
EP1151010B1 (en) | 2005-10-26 |
CA2362098C (en) | 2011-10-11 |
WO2000046251A2 (en) | 2000-08-10 |
US20150307595A1 (en) | 2015-10-29 |
ATE307830T1 (de) | 2005-11-15 |
DE60023451T2 (de) | 2006-07-20 |
EP1151010A2 (en) | 2001-11-07 |
JP2012072184A (ja) | 2012-04-12 |
JP6073550B2 (ja) | 2017-02-01 |
DK1151010T3 (da) | 2006-01-09 |
ES2250105T3 (es) | 2006-04-16 |
WO2000046251A3 (en) | 2001-01-11 |
US20080299112A1 (en) | 2008-12-04 |
AU2907200A (en) | 2000-08-25 |
DE60023451D1 (de) | 2005-12-01 |
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